In the United States, injection drug use is the principal route of hepatitis C virus (HCV) transmission and most persons who inject illicit drugs (IDUs) have HCV infection. The chief medical consequence of HCV infection is liver failure, which occurs after a progressive accumulation of fibrosis, a process that currently can only be detected reliably by biopsy. By carefully evaluating (including a liver biopsy) a random sample of 210 community-based, HCV-infected IDUs, we learned that some IDUs met published treatment criteria but almost none had been treated and that passive methods of counseling and referral did not improve treatment acquisition. These findings have led us to investigate methods to improve care delivery by (1) intensive case-management of the subset of IDUs that most need treatment and (2) detection of that subset by testing minimally-invasive markers of significant liver fibrosis. In this grant, we propose using the unique resources already established to expand our understanding of liver fibrosis progression among IDUs. The first aim is to evaluate demographic and behavioral markers of fibrosis progression. By the start of this investigation, a second liver biopsy will have been done on IDUs from the original group of 210. The rate of progression of liver fibrosis will be calculated according to gender, age, alcohol use history, and HIV infection status by subtracting the fibrosis score of the first from the second biopsy and dividing by the years between. The second aim is to develop blood markers of fibrosis progression, using a repository of sera collected every six months and at the biopsy visits. The third aim is to expand our understanding of fibrosis progression by carefully comparing viral sequence evolution and adaptive immune responses for a subset of IDUs with a high fibrosis progression rate and controls with low rates of progression. Collectively, this research will expand our understanding of liver fibrosis progression, substantially improving our ability to identify HCV-infected IDUs who are at greatest risk of disease. A high likelihood of success is anticipated since the work builds on precious existing resources and will be performed by a team of investigators who have already demonstrated the necessary skills.